Cumulative Subject reduction

TMPT activity in human erythrocytes is transmitted as an autosomic codominant trait [15] and is trimodally distributed, with 89-94% of the individuals having high, 6-11% intermediate, and 0.3% low activity [7, 15-17] (Figure 14.2). The measurement of TPMT activity in erythrocytes closely reflects the ability of bone marrow to inactivate 6-MP. TPMT activity is inversely related to erythrocyte 6-TGN levels [7, 13, 18, 19], and children with low TPMT activity and very high 6-TGN levels experienced profound myelotoxicity [20, 21]. Moreover, TPMT phenotype in erythrocyte reflects that in leukemic blasts [22]. Patients with intermediate TPMT activity had a 5-fold greater cumulative incidence of dose reductions than subjects with high activity [13], and TPMT activity has been inversely related to the time of treatment withdrawal due to cytopenia [21]. 

In a study of plasma concentrations of 33 amino acids, 159 subjects were recruited, of whom 107 were ecstasy users (93). The subjects were grouped according to cumulative lifetime use under 100 tablets (n = 34), 100-499 tablets (n = 42), 500-2500 tablets (n = 30), abstinent subjects (n = 11), and never users (n = 41). All were ecstasy free for at least 3 days, as verified by toxicological analysis. In 49% of the users, the time to the last use of ecstasy was 1 month or less. There were significant reductions in the serum concentrations of phosphoserine, glutamate, citrul-line, methionine, tyrosine, and histidine. Based on findings from other studies, the authors speculated that the reductions in serine and methionine may underlie psychosis associated with the use of ecstasy. Reduced glutamate may also add to the burden of psychiatric symptoms in ecstasy users. 

Wheat bran 7.5 g twice daily caused a small 10% reduction in the plasma digoxin levels of 14 geriatric patients after 2 weeks, but there was no significant change after 4 weeks. Bran fibre 11 g caused a 6 to 7% reduction in the absorption and the steady-state serum levels of digoxin in 16 healthy subjects." The cumulative urinary recovery of a single oral dose of... 

Aerosolised amikacin was used to treat pulmonary nontuberculous mycobacterial infection at a dose of 300 mg twice per day via a nebuliser. A cumulative dose of 35,000mg was administered over the trial period. No significant effects on nephro- or ototoxicity were seen. A hoarse voice and a bitter taste reported by one subject required a dose reduction to lOOmg [5 ]. Although a small cohort, this study supports the safety of nebulised amikacin in these patients. 

---